Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice.

Abstract

BACKGROUND & AIMS:

Interleukin-10 knockout (IL-10(-/-)) mice spontaneously develop colitis characterized by T-helper cell type 1-polarized inflammation. We tested the possible therapeutic activity of the peroxisome proliferator-activated receptor alpha (PPARalpha) ligand fenofibrate, and the PPARdelta ligand GW0742, in IL-10(-/-) mice and investigated the cellular/molecular mechanisms for fenofibrate action.

METHODS:

The effect of fenofibrate or GW0742 on the progression of colitis in C3H.IL-10(-/-) mice was evaluated. Effects of fenofibrate on cytokine and chemokine gene expression were studied in cultured splenocytes, pathogenic T cells isolated from C3H/HeJBir mice, and HT-29 colorectal cancer cells.

RESULTS:

Treatment of C3H.IL-10(-/-) mice with fenofibrate delayed the onset of colitis, decreased the colonic histopathology score, and decreased colonic expression of genes encoding the inflammatory cytokines interferon-gamma and interleukin (IL)-17. The target for fenofibrate, PPARalpha, was expressed in lymphocytes, macrophages, and crypt and surface epithelial cells of the colon. The mean number of lymphocytes was decreased by more than 75% in colonic sections of fenofibrate-treated as compared with control IL-10(-/-) mice, and fenofibrate repressed interferon-gamma and IL-17 expression in isolated T cells. Fenofibrate also repressed the expression of the genes encoding 3 chemokines, CXCL10, CCL2, and CCL20, and repressed CXCL10 gene promoter activity in tumor necrosis factor-alpha-treated HT-29 cells. In contrast to the beneficial effect of fenofibrate, the PPARdelta ligand GW0742 accelerated the onset of colitis in IL-10(-/-) mice.

CONCLUSIONS:

The immunopathology observed in IL-10(-/-) mice resembles that seen in Crohn's disease. The novel therapeutic activity of fenofibrate in this mouse model suggests that it may also have activity in Crohn's disease.

• Authors: Jimmy W Lee, Poonam J Bajwa, Monica J Carson, Daniel R Jeske, Yingzi Cong, Charles O Elson, Christian Lytle, Daniel S Straus
• Journal: Gastroenterology (Gastroenterology) Vol. 133 Issue 1 Pg. 108-23 (Jul 2007) ISSN: 0016-5085 [Print] United States
• PMID: 17631136 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL10
• Chemokines, CXC
• Hypolipidemic Agents
• Interleukin-17
• PPAR alpha
• Thiazoles
• Interleukin-10
• (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
• Interferon-gamma
• Fenofibrate

Topics

• Age Factors
• Animals
• Cell Count
• Chemokine CXCL10
• Chemokines, CXC (genetics, metabolism)
• Colitis (drug therapy, immunology, physiopathology)
• Crohn Disease (drug therapy, immunology, physiopathology)
• Disease Models, Animal
• Fenofibrate (pharmacology)
• Gene Expression (drug effects, immunology)
• HT29 Cells
• Humans
• Hypolipidemic Agents (pharmacology)
• Interferon-gamma (genetics, metabolism)
• Interleukin-10 (genetics)
• Interleukin-17 (genetics, metabolism)
• Mice
• Mice, Inbred C3H
• Mice, Knockout
• PPAR alpha (metabolism)
• Spleen (cytology)
• Th1 Cells (drug effects, metabolism)
• Thiazoles (pharmacology)